Abstract
The noncanonical nuclear factor κB (ncNFκB) pathway regulates the expression of chemokines required for secondary lymphoid organ formation and thus plays a pivotal role in adaptive immunity. Whereas ncNFκB signaling has been well described in stromal cells and B cells, its role and regulation in T cells remain largely unexplored. ncNFκB activity critically depends on the upstream NFκB-inducing kinase (NIK). NIK expression is negatively regulated by the full-length isoform of TNF receptor-associated factor 3 (Traf3) as formation of a NIK-Traf3-Traf2 complex targets NIK for degradation. Here we show that T cell-specific and activation-dependent alternative splicing generates a Traf3 isoform lacking exon 8 (Traf3DE8) that, in contrast to the full-length protein, activates ncNFκB signaling. Traf3DE8 disrupts the NIK-Traf3-Traf2 complex and allows accumulation of NIK to initiate ncNFκB signaling in activated T cells. ncNFκB activity results in expression of several chemokines, among them B cell chemoattractant (CxCL13), both in a model T cell line and in primary human CD4(+) T cells. Because CxCL13 plays an important role in B cell migration and activation, our data suggest an involvement and provide a mechanistic basis for Traf3 alternative splicing and ncNFκB activation in contributing to T cell-dependent adaptive immunity.
Highlights
Many pre-mRNAs are alternatively spliced upon T cell activation, but functional implications remain largely unexplored
Traf3DE8 disrupts the NFB-inducing kinase (NIK)-TNF receptor-associated factor 3 (Traf3)-Traf2 complex and allows accumulation of NIK to initiate noncanonical nuclear factor B (ncNFB) signaling in activated T cells. ncNFB activity results in expression of several chemokines, among them B cell chemoattractant (CxCL13), both in a model T cell line and in primary human CD4؉ T cells
Traf3 Exon 8 Is Alternatively Spliced during Activation of Jsl1 T Cells—In a recent RNA-Seq approach we found Traf3 to undergo a profound change in isoform expression upon PMAactivation of Jsl1 T cells (Fig. 1 and Ref. 3)
Summary
Many pre-mRNAs are alternatively spliced upon T cell activation, but functional implications remain largely unexplored. A role of such splicing events in regulating functional changes has been investigated in only very few cases leaving the question to which extent alternative splicing contributes to T cell biology largely unanswered This is true for other model systems, where, despite the growing evidence pointing to alternative splicing as a substantial source of proteome diversity, functional implications are only beginning to be addressed. Our data suggest a model in which Traf alternative splicing contributes to the regulation of the T cell-dependent immune response by activating ncNFB signaling and chemokine expression to participate in B cell chemoattraction and activation
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